Osteoarticular tuberculosis of the ankle, a rare localization: a case report

Tuberculosis poses a considerable public health problem in countries where the disease is endemic. Osteoarticular tuberculosis represents 3–5 % of all tuberculosis cases and 10–15 % of extra-pulmonary tuberculosis cases. Involvement of the foot and ankle is rarer. We report a case of osteoarticular tuberculosis of the ankle in a 71-year-old patient with type 2 diabetes and hypertension who presented to the trauma department of the Mohammed V Military Hospital with a painful swelling of the ankle. Standard X-rays and computed tomography scans of the ankle showed inflammatory involvement of the bone and joints. Antitubercular therapy was instituted. Given the context of endemicity, any atypical presentation of lingering bone lesions should raise the suspicion of an osteoarticular tuberculosis in order to ensure early therapeutic management.


INTRODUCTION
Tuberculosis represents a significant public health problem and ranks among the top 10 causes of death worldwide.According to the World Health Organization (WHO), Morocco reported nearly 35 000 cases of tuberculosis in 2021.
Osteoarticular tuberculosis accounts for a relatively small percentage of all tuberculosis cases, approximately 3-5 %, and a larger proportion, around 10-15 %, of extrapulmonary tuberculosis cases [1,2].Among the osteoarticular manifestations, tuberculous spondylodiscitis is the most common, accounting for approximately 50 % of cases, followed by tuberculous arthritis and extra-vertebral tuberculous osteomyelitis [3].In contrast, involvement of the foot and ankle is rarer [4,5].
In this report, we present a rare case of osteoarticular tuberculosis affecting the ankle of a 71-year-old patient with diabetes and hypertension.We also underline the importance of molecular biology techniques in the early diagnosis and management of such uncommon pathologies.

CASE REPORT
The case involved a 71-year-old patient with a medical history of type 2 diabetes, hypertension and right hemiparesis due to a prior ischaemic stroke, without any surgical or allergic history, and no known exposure to tuberculosis.The patient was admitted with swelling in the right ankle that had been present for over a month, with no history of trauma.The patient did not report any signs of infection, such as cough, burning during urination or diarrhoea, nor signs of tuberculosis infection such as fatigue, fever or night sweats.
Clinical examination revealed an afebrile patient with normal conjunctivae.At the ankle level, there was warm, red, fluctuant and painful swelling.Joint mobilization was painful.
Neurologically, the patient was conscious (Glasgow Coma Scale score of 15/15), well-oriented in time and space, and did not exhibit any sensory or motor deficits.Pupils were equal and reactive.
On respiratory examination, the respiratory rate was 18 cycles per minute, with no cyanosis, digital clubbing or thoracic deformities observed.There were no signs of respiratory distress or paradoxical breathing.Breath sounds on lung and chest examination were clear, and oxygen saturation was at 94 %.
The patient was haemodynamically stable with a blood pressure of 120/50 mmHg, showing no signs of hypoperfusion, and had a regular and strong pulse with a heart rate of 74 beats per minute.Regarding cardiac auscultation, both the first heart sound (S1) and the second heart sound (S2) were clearly audible.
On a biological level, the complete blood count (CBC) showed lymphopenia at 0.5 G l −1 and normochromic microcytic anaemia at 9.5 g dl −1 , while the remaining CBC data showed no abnormalities.The peripheral blood smear was normal with no atypical cells.Fibrinogen level was at 9.1 g l −1 .The activated partial thromboplastin time (APTT) ratio and prothrombin time (PT) were 1.6 and 61 %, respectively.
On renal examination, urea and creatinine levels were normal at 0.25 g l −1 and 6 mg l −1 , respectively.C-reactive protein (CRP) was 138.7 mg l −1 , and total proteins were 58 mg l −1 .No hydro-electrolytic abnormalities were found in the blood electrolyte panel.Liver function was normal, with aspartate aminotransferase (ASAT) at 8 IU l −1 and alanine aminotransferase (ALAT) at 12 IU l −1 .Serology for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) were all negative.
On day 1 of admission, the patient underwent joint drainage with a lavage procedure for abscess evacuation, during which pus and joint lavage fluid were collected for cytobacteriological analysis.Direct examination of the deep pus and lavage fluid, stained by Gram's method, revealed an inflammatory cellular response primarily consisting of polynuclear leukocytes with a more significant presence in the pus.No bacterial flora was detected.
The samples were cultured on Columbia agar with 5 % sheep blood, on Polyvitex chocolate agar and in Brain-Heart Infusion (BHI) broth for enrichment, which was then subcultured onto blood agar.Incubation was performed aerobically at 37 °C for 18-24 h.Schaedler agar and Columbia blood agar supplemented with nalidixic acid and colistin were inoculated and incubated anaerobically at 37 °C for 48 h.Anaerobic conditions were achieved using an anaerobic jar (Oxoid) and an anaerobic gas-generating system (Anaerogen; Oxoid).Observation of the culture plate was done every 24 h for cultures incubated aerobically and every 48 h for cultures incubated anaerobically.After 15 days of incubation, all cultures and subcultures returned as sterile.
On day 21, due to the lack of clinical improvement, the patient underwent a second procedure for joint drainage and lavage.Due to the persistent sterility of the cultures and the chronic nature of the lesion, the pus and joint washing fluid were sent to the microbiology lab where a search for mycobacteria was conducted in addition to the standard cytobacteriological examination to search for common pathogens.For the latter, the culture media used were the same as previously mentioned and were incubated and examined in the same manner.All of the media returned sterile results.
Mycobacterial testing was conducted on the lavage fluid and revealed acid-fast bacilli (AFB) on direct examination (Fig. 1) using the Ziehl-Neelsen staining method (1-10 AFB per 100 fields).Cultures on solid Löwenstein-Jensen medium and in liquid MGIT (Mycobacteria Growth Indicator Tube) medium were positive at day 21 and day 10, respectively.Real-time PCR (GeneXpert MTB/RIF; Cepheid) detected the Mycobacterium tuberculosis complex at very low levels with no detection of rifampicin resistance.
Soft tissue ultrasound revealed a poorly defined hypoechoic, heterogeneous swelling that extended into the joint, with infiltration of the muscular and tendinous structures.This suggested a complicated abscessed tenosynovitis and myositis.
Computed tomography (CT) scan of the ankle showed diffuse infiltration of the soft tissues with significant gas extending from subcutaneous soft tissues and penetrating between bone structures (Fig. 2).
A thoracic CT scan, conducted at the request of the pulmonologist to investigate the extent of the disease, revealed a bilateral pleural effusion which was notably more pronounced on the right side (Fig. 3).The limited amount of pleural fluid made it impossible to perform a puncture.
Following detection of the M. tuberculosis complex, a multidisciplinary collaboration involving a pulmonologist, traumatologist and microbiologist took place to discuss treatment.The therapeutic decision was to initiate anti-tuberculosis treatment in accordance with Morocco's national tuberculosis control programme.The treatment was successful, resulting in significant clinical, biological and radiological improvement.

DISCUSSION
Tuberculous osteoarthritis typically arises from haematogenous dissemination originating from an initial infection, often in the lungs, lymph nodes or another organ.This primary infection can be either symptomatic or asymptomatic [5].Osteoarticular tuberculosis predominantly manifests in immunocompromised individuals, such as those with HIV infection, undergoing corticosteroid therapy, receiving immunosuppressive treatments, having diabetes or with chronic renal failure.This condition exhibits a bimodal age distribution, with a peak occurrence at around 55 years in native populations and another peak between 20 and 35 years among immigrants [6].The least common location is the ankle, accounting for less than 1-6 % of cases [7].
The atypical location, subtle clinical presentation, initial absence of a diagnosis of pulmonary tuberculosis and the presence of hemiparesis collectively contributed to the delayed diagnosis in this case.Typical tuberculosis impregnation signs such as night sweats and general deterioration are infrequent.Instead, the primary clinical manifestations are pain, swelling and functional impairment [8].The chronic nature suggests a probable tuberculous aetiology.
Chest X-ray and CT scans lack specificity in such cases.In fact more than 80 % of patients do not have concomitant active tuberculosis [9,10].Standard ankle radiography and ankle CT scans are also non-specific [9,10].However, these examinations are valuable in detecting lesions and assisting in determining their nature.Magnetic resonance imaging is the preferred imaging examination as it offers the advantage of early detection, starting from the initial stages of infection, allowing for visualization of affected bone structures and their extension into surrounding soft tissues and adjacent joints [8].
In our case, the appearance of the thoracic CT scan was suggestive of pleurisy, raising the suspicion of a tuberculous origin.An anatomopathological study, while specific, was not conducted due to the purulent nature of the sample.
Laboratory tests revealed the presence of an inflammatory syndrome.Elevated CRP and fibrinogen levels and a significant cellular reaction in the pus and joint washing fluid, coupled with sterile cultures, prompted the investigation for Koch's bacillus using molecular methods and as well as conventional classical methods.In cases of extrapulmonary tuberculosis, samples often contain few bacteria (paucibacillary), highlighting the importance of molecular methods.These methods offer high sensitivity and specificity (92-98 %) for diagnosing the M. tuberculosis complex, provide rapid results (within 2 h) and exhibit a strong positive predictive value for detection of rifampin resistance (98 %) [11].Direct examination and culture remain essential components of the diagnostic process.Culture on solid media provides strains for in-depth studies, particularly in cases of therapeutic failure where exploring drug resistance is crucial.Additionally, culture in liquid media compensates for the slow growth observed on solid media.A positive direct examination confirms the presence of Mycobacterium spp.by visualizing AFB.
Treatment depends primarily on anti-bacillary drugs, which serve to inhibit the progression toward potential sequelae, such as chronic pain and deformity [8].In most cases, lesions tend to heal within 6-12 weeks with appropriate medical treatment [12].Surgical treatment is recommended when medical treatment fails, and when there are persistent issues such as synovitis, fistulas or abscesses [8].With the introduction of four-drug anti-tuberculosis chemotherapy, surgical indications have become highly limited and selective.They are focused primarily on preventing or correcting deformities and enhancing the function of the affected joint [12].Arthrodesis procedures are primarily recommended for the foot and ankle [8].In an endemic context, any unusual presentation of persistent bone lesions should prompt a suspicion of osteoarticular tuberculosis to ensure timely therapeutic intervention.The management of osteoarticular tuberculosis is multidisciplinary and necessitates coordination among physicians, bacteriologists and surgeons.

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Author's response to editor
We would like to thank all the reviewers for their valuable comments and suggestions.Please find below our point-by-point responses to the comments.
These are the answers to the Editor comments and suggestions: • Please provide more detailed description for the images, with arrows pointing to areas of interest.In your revision, please include more up-to-date literature for your references (see point 4 reviewer 1).Consider re-organising the narrative and include more details in parts as specified by the reviewer comments.
o Answer: thank you for this comment.It has been modified.

Author's response to reviewer 1
We would like to thank all the reviewers for their valuable comments and suggestions.Please find below our point-by-point responses to the comments.
These are the answers to the reviewer 1 comments and suggestions:

Description of the case:
Answer:Thank you for your comment.It has been taken into consideration.I have incorporated additional details related to the clinical examination (Lines 39 to 56), as per your suggestion.Furthermore, I have restructured the narrative within the Observation section and provided further elaboration on the laboratory findings (Lines 57 to 90).

Presentation of results :
Answer:Thank you for this comment.I have added the corresponding arrows to indicate the lesions observed on the radiological images.(Figure 2 and 3)

How the style and organization of the paper communicates and represents key findings
Answer:Thank you for this comment.I have revised the terminology and reduced redundancy in the manuscript

Literature analysis or discussion:
Answer:Thank you for this comment.I have updated the references to include more recent sources.I have also included articles mentioning the rare nature of ankle tuberculosis (lines 34 and 117) Author's response to reviewer 2 We would like to thank all the reviewers for their valuable comments and suggestions.Please find below our point by point responses to the comments.
These are the answers to the reviewer 2 comments and suggestions:

A.1) line 50-"The patient did not present any signs of tuberculosis infection". Please broaden the signs of tuberculous infection such and such or does it mean any systemic constitutional symptoms? Please clarify and broaden.
Answer:thank you for this comment.I have described the signs of tuberculosis infection.Signs of tuberculosis infection refer to the symptoms commonly found in this disease (line 43)

2) Examination should have included systemic examination -especially chest examination even if it was normal as this will be the first thing to ask how the chest sounds like. And, can I know what the indication of doing CT chest scan was? Was it because the chest auscultation was abnormal or was something else suspected such as cancer? Is it a normal practise there?
Answer:Thank you for this comment.It has been taken into consideration.I have added details of the clinical examination within the observation.(Lines 39 to 56) The chest examination did not report any anomalies.As mentioned in the paper, the CT chest scan was performed at the request of the pulmonologist as part of an extended investigation to identify the initial site of tuberculosis (line 98) 3) Was there any radiologist comment on CT chest scan finding on "diffuse bronchial micro nodules"?Did you discuss with respiratory physician regarding bilateral pleural effusion for the possibility of pleural tap and sampling?Even if there was no discussion such, please mention.
Answer:Thank you for your comment.Actually, "the diffuse bronchial micronodules" was the commentary of the radiologist.The discussion with the respiratory physician led to the decision not to perform a sampling due to the low quantity of pleural fluid 4) Last but not least, please mention if the case has been discussed and managed among multidisciplinary team as I gathered the patient presented to trauma centre in the first place so I presumed that later it would have been managed under physician or joint collaboration with physicians/Infectious diseases team etc.The practice/system might be a bit different from place to place, but if possible, please mention if there was collaboration or joint management.
Answer:Thank you for your comment, it has been taken into consideration.Yes, a collaboration between microbiologists, pulmonologists, and traumatologists took place, during which the treatment was discussed.(line 99) The patient underwent surgery twice for joint lavage on October 4, 2023, and October 25, 2023.During the first procedure, the physician requested a classic cytobacteriological examination only.However, due to persistent symptoms and after the second surgical procedure, in collaboration with the clinician, we performed a Mycobacteriological analysis.

Comments:
A. Description of the case overall is ok, but need more details: 1) line 50-"The patient did not present any signs of tuberculosis infection".Please broaden the signs of tuberculous infection such and such or does it mean any systemic constitutional symptoms?Please clarify and broaden.2) Examination should have included systemic examination -especially chest examination even if it was normal as this will be the first thing to ask how the chest sounds like.And, can I know what the indication of doing CT chest scan was?Was it because the chest auscultation was abnormal or was something else suspected such as cancer?Is it a normal practise there?3) Was there any radiologist comment on CT chest scan finding on "diffuse bronchial micro nodules"?Did you discuss with respiratory physician regarding bilateral pleural effusion for the possibility of pleural tap and sampling?Even if there was no discussion s such, please mention.4) Last but not least, please mention if the case has been discussed and managed among multidisciplinary team as I gathered the patient presented to trauma centre in the first place so I presumed that later it would have been managed under physician or joint collaboration with physicians/Infectious diseases team etc.The practice/ system might be a bit different from place to place, but if possible, please mention if there was collaboration or joint management.B. Presentation of results overall is ok.However, in line 108, "The atypical location, the insidious clinical presentation, the lack of an initial diagnosis of pulmonary 109 tuberculosis, as well as the hemiparesis, explains the delayed diagnosis" --the case did not give an enough evidence of delayed diagnosis.I gathered from case description that the patient had ONLY a month history of ankle pain and swelling, then admitted, and the team performed examination, scans, surgery and sampling, then got diagnosis with ZN stain and Gene Expert straight away, which all means quite straight forward and fast.Can you clarify this? C. Academic writing style, references and literature reviews are good.

Please rate the quality of the presentation and structure of the manuscript Satisfactory
To what extent are the conclusions supported by the data?

Fig. 2 .
Fig. 2. Axial ankle CT (a and b) scan showing diffuse infiltration of the soft tissues (red arrows) with significant gas extending from subcutaneous soft tissues and penetrating between bone structures (blue arrows).Note loss of cutaneous substance (white arrows).

Fig. 3 .
Fig. 3. Axial CT scan mediastinal (a, b and c) and lung (d) windows showing bilateral pleural effusion (blue arrows) which is more pronounced on the right side.
and swelling, then admitted, and the team performed examination, scans, surgery and sampling, then got diagnosis with ZN stain and Gene Expert straight away, which all means quite straight forward and fast.Can you clarify this?Answer:Thank you for your comment.I have added more details in the observation section to explain the diagnostic delay (lines 66 and 79).The patient was admitted on October 4, 2022 (Day 1), and the diagnosis was made on October 29, 2022 (Day 25).
[5]s there a potential financial or other conflict of interest between yourself and the author(s)?NoIf this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?Yes Nova Southeastern University -Fort Lauderdale/Davie Campus: Nova Southeastern University, UNITED STATES https://orcid.org/0000-0002-4359-5951Datereportreceived:08July2023Recommendation:Major Revision Comments: 1. Description of the case(s) The description of the case is very succint, compared to the extension of the discussion.Temporally, the case is poorly described, with just the mention of 1 month of disease.A natually flow, would have been anamnesis, examination, then labs, images, but authors describe the very few lab results last.2.Presentation of results Description of the images does not seem to correlate with what is shwon.For example, inclusion of arrows could help the reader (like this one) to see the pleural effusions they are mentioning (I can't see any). 3. How the style and organization of the paper communicates and represents key findings Use of unusual terminology makes the narrative sound odd.The paper is redundant at various places.4.Literature analysis or discussion They mention "...Involvement of the foot and ankle is rarer[5]."whichisareferencefrom1991.I just did a quick google search, and only in the past 5 years there are more than 10 TB cases of the ankle published.A search in ncbi yielded an even longer list: https://www.ncbi.nlm.nih.gov/pmc/?term=tuberculosis+anklePleaserate the quality of the presentation and structure of the manuscript PoorTo what extent are the conclusions supported by the data?Partially supportDo you have any concerns of possible image manipulation, plagiarism or any other unethical practices?NoIs there a potential financial or other conflict of interest between yourself and the author(s)?NoIf this manuscript involves human and/or animal work, have the subjects been treated in an ethical manner and the authors complied with the appropriate guidelines?Yes Strongly supportDo you have any concerns of possible image manipulation, plagiarism or any other unethical practices?